(4Z,7Z,10Z,13Z,16Z,19Z)-N-(2-mercaptoethyl)docosa-4,7,10,13,16,19-hexaenamide

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 脂肪酰基
• 英文名称: (4Z,7Z,10Z,13Z,16Z,19Z)-N-(2-mercaptoethyl)docosa-4,7,10,13,16,19-hexaenamide
• 英文别名: (4Z,7Z,10Z,13Z,16Z,19Z)-N-(2-sulfanylethyl)docosa-4,7,10,13,16,19-hexaenamide
• 化学式: C₂₄H₃₇NOS
• 分子量: 387.63
• InChiKey: NCEJSVACWMDNJW-KUBAVDMBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.2
• 重原子数：
  27
• 可旋转键数：
  16
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  30.1
• 氢给体数：
  2
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  (4Z,7Z,10Z,13Z,16Z,19Z)-N-(2-mercaptoethyl)docosa-4,7,10,13,16,19-hexaenamide 在 recombinant enzyme FAAH-1 、 三乙胺 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 甲醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 22.0h， 生成 5-((2-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido)ethyl)disulfaneyl)-2-nitrobenzoic fcid
  参考文献：
  名称：

  Fatty Acid Cysteamine Conjugates as Novel and Potent Autophagy Activators That Enhance the Correction of Misfolded F508del-Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)

  摘要：

  A depressed autophagy has previously been reported in cystic fibrosis patients with the common F508del-CFTR mutation. This report describes the synthesis and preliminary biological characterization of a novel series of autophagy activators involving fatty acid cysteamine conjugates. These molecular entities were synthesized by first covalently linking cysteamine to docosahexaenoic acid. The resulting conjugate 1 synergistically activated autophagy in primary homozygous F508del-CFTR human bronchial epithelial (hBE) cells at submicromolar concentrations. When conjugate 1 was used in combination with the corrector lumacaftor and the potentiator ivacaftor, it showed an additive effect, as measured by the increase in the chloride current in a functional assay. In order to obtain a more stable form for oral dosing, the sulfhydryl group in conjugate 1 was converted into a functionalized disulfide moiety. The resulting conjugate 5 is orally bioavailable in the mouse, rat, and dog and allows a sustained delivery of the biologically active conjugate 1.

  DOI：

  10.1021/acs.jmedchem.6b01539
• 作为产物：
  描述：

  (4Z,4'Z,7Z,7'Z,10Z,10'Z,13Z,13'Z,16Z,16'Z,19Z,19'Z)-N,N'-(disulfanediylbis(ethane-2,1-diyl))bis(docosa-4,7,10,13,16,19-hexaenamide) 在 sodium hydroxide 、 Cleland's reagent 作用下， 以 乙醇 、 水 为溶剂， 反应 0.5h， 生成 (4Z,7Z,10Z,13Z,16Z,19Z)-N-(2-mercaptoethyl)docosa-4,7,10,13,16,19-hexaenamide
  参考文献：
  名称：

  Fatty Acid Cysteamine Conjugates as Novel and Potent Autophagy Activators That Enhance the Correction of Misfolded F508del-Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)

  摘要：

  A depressed autophagy has previously been reported in cystic fibrosis patients with the common F508del-CFTR mutation. This report describes the synthesis and preliminary biological characterization of a novel series of autophagy activators involving fatty acid cysteamine conjugates. These molecular entities were synthesized by first covalently linking cysteamine to docosahexaenoic acid. The resulting conjugate 1 synergistically activated autophagy in primary homozygous F508del-CFTR human bronchial epithelial (hBE) cells at submicromolar concentrations. When conjugate 1 was used in combination with the corrector lumacaftor and the potentiator ivacaftor, it showed an additive effect, as measured by the increase in the chloride current in a functional assay. In order to obtain a more stable form for oral dosing, the sulfhydryl group in conjugate 1 was converted into a functionalized disulfide moiety. The resulting conjugate 5 is orally bioavailable in the mouse, rat, and dog and allows a sustained delivery of the biologically active conjugate 1.

  DOI：

  10.1021/acs.jmedchem.6b01539

文献信息

• [EN] FATTY ACID CYSTEAMINE CONJUGATES AND THEIR USE AS ACTIVATORS OF AUTOPHAGY<br/>[FR] CONJUGUÉS CYSTÉAMINE-ACIDE GRAS ET LEUR UTILISATION COMME ACTIVATEURS DE L'AUTOPHAGIE
  申请人：CATABASIS PHARMACEUTICALS INC

  公开号：WO2016086103A1

  公开（公告）日：2016-06-02

  The invention relates to (i) 6-membered heteroaryl substituted fatty acid cystamine conjugates, compositions thereof, methods of treating diseases involving dysregulation of autophagy, such as cystic fibrosis, idiopathic pulmonary fibrosis (IPF), a neurodegenerative disease, inflammatory disease, liver disease, muscle disease, infection and immune disease with this compound, or (ii) a method of treating idiopathic pulmonary fibrosis, mitochondrial diseases, Leigh Syndrome, Diabetes Mellitus and Deafness (DAD), Leber's hereditary optic neuropathy, Neuropathy-ataxia-retinis pigmentosa and ptosis (NARP), myoneurogenic gastrointestinal encephalopathy (MNG1E), myoclonic epilepsy with ragged red fibers (MERRF), or mitochondrial myopathy- encephalomyopathy-lactic acidosis stroke like symptoms (MELAS), comprising administering to a patient the fatty acid cysteamine conjugate, (4Z, 7Z. 10Z, 13Z, 16Z, 19Z)-N-(2-mercaptoethyl) docosa-4,7,10,13,16,19-hexaenamide or (5Z,8Z, 11Z, 14Z, 17Z)-N-(2-mercaptoethyl) icosa-5, 8,11,14, 17-pentaenamide.

  该发明涉及（i）6-成员杂环芳基取代脂肪酸半胱氨酸共轭物，其组合物，治疗涉及自噬失调的疾病的方法，如囊性纤维化，特发性肺纤维化（IPF），神经退行性疾病，炎症性疾病，肝病，肌肉疾病，感染和免疫疾病，使用该化合物，或（ii）治疗特发性肺纤维化，线粒体疾病，利氏综合征，糖尿病和耳聋（DAD），莱伯遗传性视神经病变，神经病性-共济失调-视网膜色素变性和上睑下垂（NARP），神经肌性胃肠病（MNG1E），带有皱纹红纤维的肌阵挛性癫痫（MERRF），或线粒体肌病-脑病-乳酸中毒性中风样症状（MELAS），包括向患者给予脂肪酸半胱氨酸共轭物，（4Z，7Z，10Z，13Z，16Z，19Z）-N-（2-巯基乙基）二十二碳四烯酰胺或（5Z，8Z，11Z，14Z，17Z）-N-（2-巯基乙基）二十碳五烯酰胺。
• [EN] BIS-FATTY ACID CONJUGATES AND THEIR USES<br/>[FR] CONJUGUÉS DE BIS-ACIDES GRAS ET LEURS UTILISATIONS
  申请人：CATABASIS PHARMACEUTICALS INC

  公开号：WO2012115695A1

  公开（公告）日：2012-08-30

  The invention relates to bis-fatty acid conjugates; compositions comprising an effective amount of a bis-fatty acid conjugate; and methods for treating or preventing cancer, a metabolic disease or a neurodegenerative disease comprising the administration of an effective amount of a bis-fatty acid conjugate.

  该发明涉及双脂肪酸共轭物；包含有效量双脂肪酸共轭物的组合物；以及治疗或预防癌症、代谢性疾病或神经退行性疾病的方法，包括给予有效量双脂肪酸共轭物的管理。
• FATTY ACID AMIDES, COMPOSITIONS AND METHODS OF USE
  申请人：Milne Jill C.

  公开号：US20130059801A1

  公开（公告）日：2013-03-07

  The invention relates to fatty acid amides; compositions comprising an effective amount of a fatty acid amide; and methods for treating or preventing cancer, a metabolic disease or a neurodegenerative disease comprising the administration of an effective amount of a fatty acid amide.

  本发明涉及脂肪酸酰胺；包含有效量的脂肪酸酰胺的组合物；以及治疗或预防癌症、代谢性疾病或神经退行性疾病的方法，其中包括给予有效量的脂肪酸酰胺。
• Fatty acid cysteamine conjugates and their use as activators of autophagy
  申请人：Catabasis Pharmaceuticals, Inc.

  公开号：US10251845B2

  公开（公告）日：2019-04-09

  The invention relates to (i) 6-membered heteroaryl substituted fatty acid cystamine conjugates, compositions thereof, methods of treating diseases involving dysregulation of autophagy, such as cystic fibrosis, idiopathic pulmonary fibrosis (IPF), a neurodegenerative disease, inflammatory disease, liver disease, muscle disease, infection and immune disease with this compound, or (ii) a method of treating idiopathic pulmonary fibrosis, mitochondrial diseases, Leigh Syndrome, Diabetes Mellitus and Deafness (DAD), Leber's hereditary optic neuropathy, Neuropathy-ataxia-retinis pigmentosa and ptosis (NARP), myoneurogenic gastrointestinal encephalopathy (MNGlE), myoclonic epilepsy with ragged red fibers (MERRF), or mitochondrial myopathy-encephalomy-opathy-lactic acidosis stroke like symptoms (MELAS), comprising administering to a patient the fatty acid cysteamine conjugate, (4Z, 7Z. 10Z, 13Z, 16Z, 19Z)—N-(2-mercaptoethyl) docosa-4,7,10,13,16,19-hexaenamide or (5Z, 8Z, 11Z, 14Z, 17Z)—N-(2-mercaptoethyl) icosa-5,8,11,14,17-pentaenamide.

  本发明涉及(i)6-元杂芳基取代的脂肪酸胱胺共轭物、其组合物、用该化合物治疗涉及自噬失调的疾病的方法，如囊性纤维化、特发性肺纤维化（IPF）、神经退行性疾病、炎症性疾病、肝病、肌肉疾病、感染和免疫疾病，或(ii)治疗特发性肺纤维化的方法、线粒体疾病、Leigh 综合征、糖尿病和耳聋（DAD）、Leber 遗传性视神经病变、神经病-共济失调-视网膜色素变性和眼睑下垂（NARP）、肌神经源性胃肠道脑病（MNGlE）、或线粒体肌病-脑肌病-乳酸中毒中风样症状（MELAS），包括给患者服用脂肪酸半胱胺共轭物（4Z、7Z.10Z、13Z、16Z、19Z）-N-（2-巯基乙基）二十二碳-4,7,10,13,16,19-六烯酰胺或（5Z、8Z、11Z、14Z、17Z）-N-（2-巯基乙基）二十二碳-5,8,11,14,17-五烯酰胺。
• USE OF INTRACELLULAR ENZYMES FOR THE RELEASE OF COVALENTLY LINKED BIOACTIVES
  申请人：Catabasis Pharmaceuticals, Inc.

  公开号：EP2685969A2

  公开（公告）日：2014-01-22